Presentation by Neil Scolding

1. North Bristol NHS
NHS Trust
University of
BRISTOL
BNI
Institute of Clinical Neurosciences
Advances in stem cell therapies in the
treatment of MS
MS Trust, Windsor, November 2015 Neil
Scolding

2. oligodendrocyte
precursors
astrocytes
brain
stem cell
stem
cells

3. oligodendrocyte
precursors
astrocytes
brain
stem cell
stem
cells
1

4. neurones
skin
heart
kidney
22
stem
cells

5. oligodendrocyte
precursors
astrocytes
brain
stem cell
cell
replacement

6. Bunge et al 1961

8. Carswell 1838

10. embryonic
oligodendrocytes
adult
oligodendrocytes
Schwann cells
olfactory glia
xenotransplants?
stem cells

11. embryonic
oligodendrocytes
adult
oligodendrocytes
Schwann cells
olfactory glia
xenotransplants?
stem cells
?

13. Scolding, Franklin et al
Brain 1998
NG2
Wilson/ Raine/Scolding
J Neuroimmunol 2006
oligodendrocyte progenitors
are not rare in MS lesions
- Wolswijk, Trapp, Dowling, Reynolds

14. Hoechst Nestin Musashi-1
Hoechst Nestin Musashi-1
BRISTOL
Institute of Clinical Neurosciences
Nestin –PDGFαR
Nestin-GFAP
Nestin-doublecortin
Nestin
Hoechst
Ki67
Nestin Ki67 Hoechst
Endogenous
neural precursors
respond to
disease
processes in MS
Snethen, Love & Scolding
Regen Med.
2008 3: 835-47.
Nestin-doublecortin
Hoechst Nestin NG2

15. Hoechst Nestin Musashi-1
Hoechst Nestin Musashi-1
BRISTOL
Institute of Clinical Neurosciences
Nestin –PDGFαR
Nestin-GFAP
Nestin-doublecortin
Nestin
Hoechst
Ki67
Nestin Ki67 Hoechst
Nestin-doublecortin
Hoechst Nestin NG2
.......These findings are important to an
understanding of the remyelination of
lesions of multiple sclerosis and imply
that transplantation of oligodendrocyte
precursor cells will probably not be an
effective therapy for multiple sclerosis.

16. Charcot 1872 Carswell 1838

17. Institute of Clinical Neurosciences
North Bristol
NHS
NHS Trust
University of
BRISTOL
ccssnnbb BNI
acute relapseacute relapse

18. Institute of Clinical Neurosciences
North Bristol
NHS
NHS Trust
University of
BRISTOL
ccssnnbb BNI
progressionprogressionacute relapseacute relapse

19. Institute of Clinical Neurosciences
North Bristol
NHS
NHS Trust
University of
BRISTOL
ccssnnbb BNI
progressionprogressionacute relapseacute relapse
axon lossaxon loss
neuron lossneuron loss

22. embryonic
oligodendrocytes
adult
oligodendrocytes
Schwann cells
olfactory glia
xenotransplants?
stem cells

23. Not so cell specific
Not so site specific
No single pathological process

24. oligodendrocyte
precursors
astrocytes
brain
stem cell
oligodendrocyte
replacement
?

25. oligodendrocyte
precursors
astrocytes
brain
stem cell
oligodendrocyte
replacement
?
‘restorative’ cell
therapy

26. oligodendrocyte
precursors
astrocytes
brain
stem cell
oligodendrocyte
replacement
cell replacement
- immune system
‘restorative’ cell
therapy

27. embryonic
oligodendrocytes
adult
oligodendrocytes
Schwann cells
olfactory glia
xenotransplants?
stem cells

29. small molecules for myelin repair
– anti-lingo antibodies
– ‘re-positioned’ drugs
• miconazole, clobetasol
• bexarotene (retinoid X-receptor
gamma agonist)

30. oligodendrocyte
precursors
astrocytes
brain
stem cell
oligodendrocyte
replacement
cell replacement
- immune system
‘restorative’ cell
therapy
small molecule therapy
for myelin repair

31. Institute of Clinical Neurosciences
North Bristol
NHS
NHS Trust
University of
BRISTOL
ccssnnbb BNI
progressionprogressionacute relapseacute relapse
axon lossaxon loss
neuron lossneuron loss

32. HSCT
HSCT

33. haematopoetic
stem cell
conditioning
e.g., carmustine,
cytarabine, etoposide, melphalan,
alemtuzumab
grafting
us. autologous
HSCT

34. haematopoetic
stem cell
conditioning
e.g., carmustine,
cytarabine, etoposide, melphalan,
alemtuzumab
grafting
us. autologous
harvesting
HSCT

35. haematopoetic
stem cell
conditioning
e.g., carmustine,
cytarabine, etoposide, melphalan,
alemtuzumab
grafting
us. autologous
harvesting/induction
cyclophosphamide
GCSF
HSCT

36. haematopoetic
stem cell
conditioning
e.g., carmustine,
cytarabine, etoposide, melphalan,
alemtuzumab
grafting
us. autologous
harvesting/induction
cyclophosphamide
GCSF
HSCT
HSCT
•80-85% reduced relapses
•mortality 1.3%-5%
•??effect on progression

37. haematopoetic
stem cell
conditioning
e.g., carmustine,
cytarabine, etoposide, melphalan,
alemtuzumab
grafting
us. autologous
harvesting/induction
cyclophosphamide
GCSF
HSCT
“autologous HSCT does not appear to
be effective against established
progressive forms of MS …. additional
trials of these protocols are probably
not indicated for patients with
progressive MS”
(Hauser, 2015)

38. oligodendrocyte
precursors
astrocytes
brain
stem cell
oligodendrocyte
replacement
haematopoeitic
stem cell therapy
HSCT
‘restorative’ cell
therapy
small molecule therapy
for myelin repair

39. HSCT
HSCT

40. adapted from: Korbling & Estrov, NEJM 2003
Adult stem cells for tissue repair - a new therapeutic concept
Bone marrow stem cells
Circulating bone marrow stem cells
enter the brain and spinal cord and
may contribute to the repair of
damaged tissue

41. Bone marrow stem cells stimulate or re-programme repair both
directly and through a range of ‘non-canonical’ mechanisms :-
• fusion
• immune modulation
• neuroprotection
• growth factor production
• reduced scar formation
• new vessel formation
• REGULATE LOCAL TISSUE STEM CELLS
• transdifferentiation
Blau, H. M. Cell fusion: A twist of fate. Nature 419, 437 (2002).
Rice CM, Scolding NJ. Adult stem cells--reprogramming neurological repair? Lancet. 2004;
364:193-199

42. Institute of Clinical Neurosciences
North Bristol
NHS
NHS Trust
University of
BRISTOL
ccssnnbb BNI
progressionprogressionacute relapseacute relapse
axon lossaxon loss
neuron lossneuron loss

43. Intravenous injection of MSCs
ameliorates EAE
Pluchino et al. Nature 2005 436: 266-71
Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory
mechanism.

44. Institute of Clinical Neurosciences
North Bristol
NHS
NHS Trust
University of
BRISTOL
ccssnnbb BNI
progressionprogressionacute relapseacute relapse
axon lossaxon loss
neuron lossneuron loss

46. Institute of Clinical Neurosciences
North Bristol
NHS
NHS Trust
University of
BRISTOL
ccssnnbb BNI
progressionprogressionacute relapseacute relapse
axon lossaxon loss
neuron lossneuron loss

47. J. Neurosci. Res. Vol.84, pp 587-595
Copyright © 2006 Wiley-Liss, Inc., A Wiley Company
Luxol fast blue and Bielshowsky silver
axon densityaxon density

49. North Bristol NHS
NHS Trust
University of
BRISTOL
BNI
Institute of Clinical Neurosciences

51. I. NEUTROPHIL MOLECULES AND FUNCTIONS
I.A. ADHESION AND MIGRATION
I.A.1. Traffic and margination
I.A.2. Adhesion to the Endothelial Wall
Rolling and Tethering
Neutrophil Priming During Rolling
Firm Adhesion and Spreading
I.A.3 Extravasation and Diapedesis Toward
Inflammatory
Stimuli
Transendothelial Migration
Migration Within Interstitial Tissues
Signaling by Chemoattractants
Transepithelial Migration
I.B. PHAGOCYTOSIS, DEGRANULATION AND
BACTERIA KILLING
I.B.1. Phagocytosis
I.B.2. Degranulation
Granule Biogenesis
Mechanisms of Degranulation
I.B.3. Microbicidal Molecules
NADPH-Derived Oxidants
The H2O2-Myeloperoxidase System
Nitric Oxide-Synthase-Derived Reactive Nitrogen
Intermediates
Granule Proteins
Antimicrobial Proteins
Proteases
I.C. CYTOKINE SYNTHESIS
I.C.1. TNF-a as a Proinflammatory Cytokine
I.C.2. IL-1 and IL-1 Receptor Antagonist (IL-1-Ra)
I.C.3. IL-8 as a Prototype of Chemokines
I.C.4. Modulation of Cytokine Expression by Neutrophils
IFN-g
IL-10
IL-4 and IL-13
I.C.5. Molecular Regulation of Cytokine Production
I.D. APOPTOSIS AND RESOLUTION OF ACUTE
INFLAMMATION
I.D.1. Progressive Decrease of Neutrophil Recruitment
I.D.2. Apoptosis in Resolution of Inflammation
II. NEUTROPHILS IN PATHOLOGY
II.A. Bacterial Infection
II.B. Tissue Injury-Induced Inflammation: Ischemia-
Reperfusion Injury
II.C. Crystal-Induced Inflammation
II.D. Complement-Induced Inflammation and Oxidative
Stress: Hemodialysis
II.E. Immune Complex-Induced Inflammation:
Antibody-Mediated Glomerunephritis
II.F. Cytokine-Induced Inflammation: Rheumatoid
Arthritis
II.G. Antineutrophil Cytoplasmic Antibodies and
Vasculitis: Autoimmunity Against Neutrophil
Components
II.H. Genetic Disorders of Neutrophil Regulations:
Hereditary Periodic Fever Syndromes
II.I. Cystic Fibrosis: The Paradox of an Exacerbation
of Neutrophil-Mediated Tissue Damage
and a Concomitant Persistence of Infection

52. adapted from: Korbling & Estrov, NEJM 2003
Circulating bone marrow stem cells
enter the brain and spinal cord and
may contribute to the repair of
damaged tissue
Bone marrow cells for tissue repair

53. adapted from: Korbling & Estrov, NEJM 2003
bone marrow cells

54. Study of Intravenous Autologous Marrow
in Multiple Sclerosis (SIAMMS)
6 participants
Mean age 48 yrs
Disease duration 16 yrs
Median EDSS 6
Intervention:
Daycase procedure
Bone marrow harvest
(250-750ml) under
general anaesthesia
Bone marrow is filtered
Intravenous infusion of
autologous marrow
cells
No myelo- or
lymphoablation
Cell dose 9 x109
TNC

55. Institute of Clinical Neurosciences
Study of Intravenous Autologous Marrow
in Multiple Sclerosis
SIAMMS – results, electrophysiology
Global EP Scores at 1 yr BM CT patients all improve p=0.02
Institute of Clinical Neurosciences

56. Intervention:
day case procedure
BM harvest (250-750ml), GA
i/v infusion, ~1010
filtered cells
no myelo-ablation
delayed vs. immediate
treatment
with generous support from the
Silverman Family Foundation
Phase II Trial
80 patients
Assessment of Bone Marrow Cell Therapy in Multiple Sclerosis
ACTiMuS
Institute of Clinical Neurosciences
BRISTOL

59. Cell therapy trials in MS
Rice, Kemp, Wilkins
& Scolding Lancet 2013
18 clinical studies reported
or known to be in progress
MSCs
Unselected marrow
Umbilical cord cells
Adipose cells
Importance of regulated
clinical trials
University of
BRISTOL
North Bristol NHS
NHS Trust
Bristol Institute of Clinical Neurosciences

60. Cell therapy trials in MS
Rice, Kemp, Wilkins
& Scolding Lancet 2013
47 clinical studies
reported or known to be in
progress
University of
BRISTOL
North Bristol NHS
NHS Trust
Bristol Institute of Clinical Neurosciences

61. oligodendrocyte
precursors
astrocytes
brain
stem cell
oligodendrocyte
replacement
haematopoeitic
stem cell therapy
HSCT
‘restorative’ cell
therapy
small molecule therapy
for myelin repair
PHASE I,II
PHASE II
PHASE I

62. Department of Neurology, University of Texas Medical School at Houston, Texas,
USA

63. The Silverman
Family Trust
MS Trust
Ataxia UK
MRC
Rosetrees
Trust
Multiple
Sclerosis
Society
Sir Halley
Stewart Trust
Friends of
Frenchay
NIHR
North Bristol
NHS Trsut
Research
Foundation